In rheumatoid arthritis (RA), bone and cartilage are invaded and destroyed by fibroblastic cells, resulting in crippling joint disease. In other systemic inflammatory diseases, such as lupus and scleroderma, fibrotic scar tissue can develop in organs, such as the lungs or kidneys, leading to severe disability or death. These diverse pathologic processes have in common the prominent involvement of fibroblasts. Although fibroblasts are normally resting cells which help maintain tissue integrity, following injury they become activated to proliferate and produce extracellular matrix in order to promote wound healing. In fibrotic processes and in RA, these normal functions have gone destructively awry. It is unclear from studies to date whether all fibroblasts participate equally in these events. We and others have described a subset of normal fibroblasts in rats and mice, characterized by the absence of the surface glycoprotein Thy- l, which share many phenotypic features of the activated fibroblasts seen in fibrosis and RA. The human equivalent of Thy-1, CD90, is also expressed on only a portion of normal fibroblasts, but the characteristic features of CD90 subpopulations have not been described. We predict that Thy-1/CD90- and Thy-1/CD90+ fibroblasts have distinct roles in tissue remodeling, and that Thy-1/CD90 expression is altered in the progression of fibrotic and arthritic lesions. Accordingly, the specific aims of the proposed investigation will be: l) To measure CD90 expression in fibroblasts derived from involved tissues in connective tissue diseases and arthritic synovium, by comparing CD90 expression in fibroblasts from fibrogenic lesions and arthritic synovium vs. normal tissues; 2) To define the differential biology of human CD9O fibroblast subpopulations, by comparing differential gene expression patterns in sorted Thy-1-/+ and CD90-/+ fibroblasts; and 3) To characterize the """"""""matrix-invasive"""""""" phenotype of CD90 fibroblast subpopulations, by measuring the migratory and invasive activity of Thy- 1/CD90-/+ fibroblasts. Information derived from these studies will add a new dimension to the current understanding of molecular mechanisms of fibroblast activation in these crippling conditions.
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